The insulin-like growth factor (IGF) system includes the insulin-like growth factors I and II (IGF-I and IGF-II), insulin, insulin receptor (IR), insulin-like growth factor receptors I and II (IGF-IR and IGF-IIR) and IGF-II/M6PR), insulin-like growth factor binding proteins (IGFBP-1 to -6), and IGFBP-related proteins (IGFBP-rPs). A schematic of this system is set forth in FIG. 1. The IGF system plays a key role in regulating both normal and pathogenic cellular growth and function.
Unlike insulin, the IGFs are produced by almost every cell in the body, although IGF-II is predominantly produced in the liver (Oh, Cancer Epidemiol Biomarkers Prev 13:748-752, 2004). In rodents, IGF-I is primarily expressed at adulthood, while IGF-II is mainly expressed prenatally. In humans, both IGFs are produced at all stages of life. High circulating levels of IGFs have been correlated with increased risk of several cancers (Peyrat et al., Eur J Cancer 29A:492-497, 1993; Chan et al., Science 279:563-566, 1998; Hankinson et al., Lancet 351:1393-1396, 1998; Wolk et al., J Natl Cancer Inst 90:911-9151998; Ma et al., J Natl Cancer Inst 91:620-625, 1999).
There are six IGFBPs, each of which binds to IGF-I and IGF-II with varying affinities. For example, IGFBP-5 and -6 bind to IGF-II with a 10-fold higher affinity than IGF-I. IGFBPs increase the half-life of circulating IGFs, and control their availability for receptor binding. IGFBP-3, the predominant IGFBP in serum, has been shown to suppress the mitogenic effect of IGF-I, and high levels of IGFBP-3 are inversely related to cancer risk (Oh et al., supra, 2004).
Recently, a number of epidemiologic studies have shown that high circulating levels of IGF-1 are associated with an increased risk for cancer, including breast, prostate, lung and colorectal cancer. IGF-1 stimulates cell proliferation and inhibits apoptosis; a combination of these effects have been shown to have a profound impact on tumor growth (reviewed in Yu and Rhan, J. Natl. Canc. Inst. 18: 1472-1849, 2000). Antibodies developed against IGF-IR have been shown to inhibit cancer cell proliferation and induce receptor degradation in tumor cells. However, there is still a need for human antibodies that bind IGF-II that can be used to detect IGF-II and can be used in treatment methods.